Overview

Name: Atomoxetine
Synonyms: ATX, Strattera
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Phase 1)
Status in Select Countries: Approved in North America, European Union, and may other countries for treatment of Attention Deficit Hyperactivity Disorder (ADHD)
Company: Eli Lilly & Co.
Approved for: ADHD in US

Background

Atomoxetine is a norepinephrine uptake inhibitor. It blocks a norepinephrine transporter and boosts noradrenaline levels in the brain. It is one of the few non-stimulant drugs used to treat attention deficit hyperactivity disorder in children, and is prescribed widely around the world. Norepinephrine is mainly produced by neurons of the locus coeruleus, a midbrain region that shows neuropathology and degeneration early in both AD and Parkinson’s disease (e.g., Jacobs et al., 2021). This and other lines of research implicate loss of noradrenaline in Alzheimer's disease (see, e.g., Dec 2010 conference news), hence atomoxetine's value as an add-on medication was investigated.

In preclinical work using the 5XFAD mice, increasing brain noradrenaline using atomoxetine and the noradrenaline precursor L-DOPS suppressed glial activation and Aβ deposition, and improved performance in the Morris water maze (Kalinin et al., 2011).

Findings

Between 2003 and 2006, Eli Lilly conducted a six-month Phase 2/3 repurposing trial at eight sites in the United States to evaluate the effectiveness of 25-80 mg/day of atomoxetine in 92 patients with mild to moderate Alzheimer's disease who were on stable doses of standard acetyl cholinesterase inhibitor therapy. Cognition as measured by the ADAS-Cog was the primary outcome of this trial. Atomoxetine in these patients was reported to be generally safe, though with an increase in heart rate; however, it did not benefit cognition in these patients (Mohs et al., 2009).

From 2012 to 2018, a Phase 2, 12-month biomarker study at Emory University assessed atomoxetine in people with mild cognitive impairment. It enrolled 39 people who had to have CSF Aβ and tau levels indicative of AD, to receive placebo or flexible doses of atomoxetine starting at 10 mg per day and increasing weekly to 100 mg or a maximum tolerated dose. In a crossover design, participants took drug or placebo for six months each, followed by an optional two-year open-label extension. Blood and CSF biomarkers were assessed at baseline, six, and 12 months. The primary outcome was change in neuroinflammation measured by CSF IL1 and thymus-expressed chemokine concentrations. Other primaries were adverse events and drop-out rate. Results are published (Levey et al., 2021). Atomoxetine treatment led to increased plasma and CSF norepinephrine concentrations, demonstrating target engagement. IL-1α and thymus-expressed chemokine were undetectable in most samples. CSF tau and p-tau181 were reduced by 5-6 percent compared to placebo, Aβ42 was unchanged. FDG-PET and functional MRI measures found increased glucose uptake and inter-network connectivity in the hippocampus and temporal lobe circuits with treatment. The differences persisted for six months after treatment. The regimen was safe and tolerable, with all but two participants reaching the 100 mg dose. Common adverse events were gastrointestinal symptoms, dry mouth, and dizziness. Other side effects were consistent with atomoxetine’s established profile and included increased heart rate, weight loss, and a trend for higher blood pressure. A proteomics analysis noted normalization of CSF biomarkers related to synaptic function, brain metabolism, and inflammation. As expected, there were no significant effects on cognition and clinical outcomes.

Atomoxetine is also being tested as a cognitive enhancer in people with Parkinson’s disease. It gave mixed results in several small trials (see analysis in Ghosh et al., 2020). One study indicated that Parkinson’s patients with low locus coeruleus volumes respond to atomoxetine (O’Callaghan et al., 2021).

For details on atomoxetine trials, see clinicaltrials.gov.

Last Updated: 24 Jan 2022

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Overview

Name: HMTM
Synonyms: LMTM, LMTX, LMT-X, TRx0237, Tau aggregation inhibitor (TAI), Methylene Blue
Chemical Name: Hydromethylthionine mesylate, Leuco-methylthioninium bis(hydromethanesulfonate)
Therapy Type: Small Molecule (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease, Frontotemporal Dementia
U.S. FDA Status: Alzheimer's Disease (Phase 3), Frontotemporal Dementia (Phase 3)
Company: TauRx Therapeutics Ltd
Approved for: Methylene Blue predates FDA. Used for treatment of malaria and methemoglobinemia.

Background

TRx0237 (LMTX™) is a second-generation tau protein aggregation inhibitor for the treatment of Alzheimer's disease (AD) and frontotemporal dementia. It is a replacement formulation for Rember ^®, the first company's first proprietary formulation of methylthioninium chloride (MTC). Both TRx0237 and Rember are derivatives of Methylene Blue, an old drug that predates the FDA and is being widely used in Africa for the treatment for malaria, as well as for methemoglobinemia and other conditions. TRx0237 and Rember share the same mode of action, but TRx0237 has been designed as a stabilized, reduced form of MTC to improve the drug's absorption, bioavailability, and tolerability.

The rationale behind this approach is that these compounds prevent tau aggregation or dissolve existing aggregates to interfere with downstream pathological consequences of aberrant tau in tauopathies including Alzheimer's and other neurodegenerative diseases. Tau pathology is widely considered to be downstream of Aβ pathology and is more closely linked to cognitive deficits in Alzheimer's disease. Mutations in the tau gene cause frontotemporal dementia, not Alzheimer's disease, but tau is considered a central drug target for all tauopathies, including Alzheimer's.

Prior to the first publicized Phase 2 trial on Rember TM in 2008, one peer-reviewed paper to support this rationale had been published, which reported that Methylene Blue interfered with the tau-tau binding necessary for aggregation (Wischik et al., 1996). In 2015, the same lab published on LMTX®, claiming a Ki of 0.12 micromolar for inhibition of intracellular tau aggregation, and a similar potency for disrupting tau aggregates isolated from AD brain (Harrington et al., 2015).

Numerous independent academic investigations of the commercially available parent compound, Methylene Blue, have reported potentially beneficial effects on a growing list of cellular and system-level endpoints, including tau fibrillization in vitro (Crowe et al., 2013), autophagy (e.g. Congdon et al., 2012), neuroprotection via mitochondrial antioxidant properties (e.g. Wen et al., 2011), as well as on Aβ clearance and proteasome function in transgenic AD mouse models (Medina et al., 2011), and spatial learning and brain metabolism in rats (Deiana et al., 2009; Riha et al., 2011). One mechanistic study found that Methylene Blue oxidizes cysteine sulfhydryl groups on tau in a way that keeps tau in the monomeric state (Feb 2013 news). Subsequently, TRx0237’s developers reported that the inhibition of tau aggregation is cysteine-independent (Al-Hilaly et al., 2018).

In preclinical work, LMTX was reported to improve learning and reduced brain tau load in two strains of tau transgenic mice (Melis et al., 2015). The compound increased cholinergic signaling, mitochondrial function, and expression of synaptic proteins and neuroprotection in mice (Kondak et al., 2023; Schwab et al., 2024; Zadrozny et al., 2024). These effects, but not tau aggregation, were blocked by chronic pretreatment with an acetylcholinesterase inhibitor or memantine (Riedel et al., 2020; Kondak et al., 2022; Santos et al., 2022). Proteomic analysis of tau mice suggested LMTX acts via tau-dependent and -independent actions (Schwab et al., 2021). These studies all originate from one lab. An independent group reported that neither Methylene Blue not LMTM protected cells in a high throughput screen for tau-mediated toxicity (Lim et al. 2023).

Some studies reported a generalized anti-aggregation effect for Methylene Blue against aggregation-prone proteins, such as prion protein and TDP-43 (e.g. Cavaliere et al., 2013; Arai et al., 2010). Other papers report no inhibition of tau- and polyglutamine-mediated neurotoxicity in vivo (see van Bebber et al., 2010). In mice overexpressing human α-synuclein, LMTM treatment reduced α-synuclein inclusions in the brain, and normalized movement and anxiety-related behaviors (Schwab et al., 2017). It did not alter glutamate release or related behaviors in these mice (Schwab et al., 2022).

According to a case report, an asymptomatic carrier of the P301S MAPT mutation remained cognitively stable and cerebral atrophy progressed more slowly than expected after 5 years on LMTM treatment during the expected time of onset of frontotemporal dementia symptoms (Bentham et al., 2021).

Findings

No information on Phase 1 trials of TRx0237 is available. A four-week Phase 2 safety study of 250 mg/day of TRx0237 in patients with mild to moderate Alzheimer's disease began in September 2012 but was terminated in April 2013, reportedly for administrative reasons.

In November 2012, TauRx started a Phase 3 study comparing 200 mg/day of LMTM to placebo in a planned 800 patients with a diagnosis of either all-cause dementia or Alzheimer's disease mild enough to score above an MMSE of 20. The trial ran at more than 90 sites in North America and Europe. As primary outcomes, it used standard cognitive (ADAS-Cog 11) and clinical (ADCS-CGIC) batteries, as well as temporal lobe brain metabolism as measured by FDG-PET and safety parameters. Results were presented—and disputed—at the 2016 CTAD meeting. Participants on LMTM declined on cognition (ADAS-Cog) and functional scales (ADCS ADL) as rapidly as did patients on placebo, which contained a low dose of active compound for coloring purposes (Dec 2016 conference news; Wilcock et al., 2018).

Another Phase 3 trial compared 150 and 250 mg/day of TRx0237 with placebo in 891 patients with mild to moderate Alzheimer's disease with an MMSE of 14 or higher. Started in 2013, this trial involved more than 80 sites in North America, Australia, Europe, and Asia. It used clinical (ADCS-CGIC), cognitive (ADAS-Cog 11), and safety measures as primary outcomes. Negative results from this trial were presented at the 2016 AAIC conference in Toronto and later published after peer review (Jul 2016 conference news; Gauthier et al., 2016).

A third Phase 3 trial evaluated TRx0237 in the behavioral variant of frontotemporal dementia, the most common form of this disease. Begun in August 2013, this trial targeted enrollment of 180 people with probable bvFTD who have frontotemporal atrophy confirmed by MRI and whose MMSE is above 20. The trial compared 200 mg/day to placebo for the drug's ability to show clinical benefit on activities of daily living as measured by the modified ADCS-CGIC Alzheimer's scale and the revised Addenbrooke's Cognitive Examination (ACE-R), a widely used psychometric tool in FTD clinical research. This trial was to be conducted at 45 sites in North America, Europe, Australia, and Singapore. At the 2016 ICFTD conference in Munich, this trial was reported to have missed its co-primary endpoints (Sep 2016 conference news; company press release). Results were published after peer review (Shiells et al., 2020).

These three Phase 3 trials used “active placebo” tablets that include 4 mg of TRx0237 as a urinary and fecal colorant to help maintain blinding; hence the "placebo" group received a total of 8 mg/day of TRx0237. TRx0237's predecessor compound, Rember TM, colors urine and feces, and the blinding of its Phase 2 trial has been questioned (see Oct 2012 news for details and Q&A with TRx0237's founding scientist, Claude Wischik). However, post-hoc pharmacokinetic analyses of the Phase 3 trials led the investigators to claim that even 8 mg daily TRx0237 was sufficient to induce changes in brain structure and function (e.g., see Schelter et al., 2019).

In January 2018, TauRx started a Phase 2/3 monotherapy trial aiming to enroll 180 people with all-cause dementia and Alzheimer's disease, at 55 sites in North America, Belgium, Poland, and the U.K. The trial compares a six-month course of 4 mg of LMTM—renamed to HMTM—twice daily. This is the daily dose of HMTM previously admixed to "active placebo'' in the prior Phase 3 trials. LMTM is compared to 4 mg Methylene Blue twice weekly. Acetylcholinesterase inhibitors or memantine are not allowed. Primary outcomes include 18F-FDG-PET imaging and safety; secondary outcomes include structural MRI, as well as measures of cognition and activities of daily living.

In September 2018, TauRx changed the trial protocol to add a third treatment arm of 8 mg HMTM twice daily. The trial increased enrollment to 375, and extended dosing to nine months. Eligibility criteria were changed to accept only people with mild cognitive impairment due to AD, a Global Clinical Dementia Rating of 0.5, and a positive amyloid PET scan. Primary outcomes were also changed, to include a composite measure of cognition and function comprising selected items from the ADAS-Cog and ADCS-ADL scales. The trial was enlarged to 147 sites in North America and Europe.

Recruitment ended in October 2019. In late 2019, the first of three listed primary outcomes was changed from 18F FDG PET to ADAS-Cog 11; the composite measure was changed to the ADSC-ADL23. The inclusion criteria were relaxed to once again include people with more advanced disease, from an earlier MMSE range of 20-27 to 16-27, from a CDR of 0.5 to now include CDR 0.5 to 2, and from excluding all epilepsy to including people with a single episode. Enrollment changed from 375 to 450, study duration changed from nine to 12 months, with a one-year open-label extension. This final protocol was published (Wischik et al., 2022).

According to a trade news report, the company announced top-line results in an October 2022 press release; however, this information is no longer available on the company web site.

According to a company presentation at the December 2022 CTAD conference, the trial failed on both primary endpoints (Medscape). In July 2023, the company showed some biomarker results at the AAIC in Amsterdam. Plasma neurofilament light was shown to have increased in the Methylene Blue control group, but not in the treated group. NfL levels reportedly correlated with trends in plasma p-tau181. At the March 2024 AD/PD conference, the company presented post hoc subgroup analyses of the MCI group, claiming that progression from a CDR of 0.5 to 1 was halved by treatment, that the ADAS-Cog11 declined less in MCI participants who had taken 16 mg per day for two years compared to those who took placebo the first year, and that, when compared to historical controls, the MCI group had declined less on the ADAS-Cog11 and preserved more brain volume over 24 months (Mar 2024 conference news).

TauRx will apply for marketing authorization for HMTM in the U.K. and is in discussions with the European Medicines Agency and Chinese regulators.

For all clinical trials with TRx0237, see clinicaltrials.gov.

Clinical Trial Timeline

Phase 2
Phase 2/3
Phase 3
Study completed / Planned end date
Planned end date unavailable
Study aborted

Sponsor	Clinical Trial	2010
TauRx Therapeutics Ltd	NCT01626391	N=9RESULTS
TauRx Therapeutics Ltd	NCT01689233	N=500
TauRx Therapeutics Ltd	NCT01689246	N=933
TauRx Therapeutics Ltd	NCT01626378	N=180
TauRx Therapeutics Ltd	NCT03446001	N=180

Last Updated: 10 May 2024

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Overview

Name: Exenatide
Synonyms: Exendin-4, Byetta, Bydureon
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease
U.S. FDA Status: Alzheimer's Disease (Inactive), Parkinson's Disease (Phase 3)
Company: AstraZeneca, Eli Lilly & Co.
Approved for: Diabetes mellitus in US

Background

Exenatide is an analog of the hormone glucagon-like peptide-1. GLP-1 stimulates the pancreas to release insulin in response to food intake. It resensitizes cells to insulin signaling and is used to treat Type 2 diabetes. The rationale of this approach is that counteracting the insulin resistance that accompanies some cases of Alzheimer's disease might confer a therapeutic benefit (e.g. Talbot et al., 2012; Talbot, 2014).

The short-acting form of exenatide is administered by twice-daily subcutaneous self-injection; a long-acting preparation is injected just once a week. In mice, exenatide readily crossed the blood-brain barrier, while other GLP-1 mimetics liraglutide and semaglutide did not (Salameh et al., 2020).

In animal models of Parkinson’s disease, exenatide dampens inflammation and protects dopaminergic neurons, which were reported to express GLP-1 receptor (Perry et al., 2002; Bertilsson et al., 2008; Cao et al., 2016; Jan 2009 news). It also had beneficial effects in a mouse model of the rapidly progressing α-synucleinopathy multiple systems atrophy (Bassil et al., 2017). Potential mechanisms of neuroprotection by GLP-1 mimetics are reviewed in Reich and Hö lscher, 2022.

In mouse models of AD, exendin-4 was reported to lower amyloid plaque load and protect against Aβ oligomers (Li et al., 2010; Gengler et al., 2012; Bomfim et al., 2012). The related GLP-1 analog liraglutide was reported to have similar effects (Dec 2010 news). Exenatide also enhanced cognition in insulin-resistant rats (Gad et al., 2016), and improved insulin receptor signaling and learning in Tg2576 mice (Robinson et al., 2019).

Findings

In 2010, an investigator-sponsored trial at University College London enrolled 44 people with moderate Parkinson's disease into an open-label study. Half the cohort injected themselves with 10 micrograms of exendin-4 twice daily for a year, in addition to taking L-dopa, while the other half took only L-dopa. Movement abilities and cognitive scores were reported to have improved in participants on drug, and declined in those on L-dopa only (Aviles-Olmos et al., 2013; Jun 2013 news). The drug was well-tolerated, although many participants lost weight. Gains in movement and cognitive skills persisted for one year after treatment ended (Aviles-Olmos et al., 2014).

From 2014 to 2016, UCL researchers ran a placebo-controlled Phase 2 trial of 2 milligrams extended-release exendin-4 administered subcutaneously once weekly for 48 weeks. This trial enrolled 60 people with moderate Parkinson's. Motor symptoms were reported to have improved in those on drug, with gains persisting for three months past dosing, whereas the placebo group declined (Athuada et al., 2017, Aug 2017 news). Again, the drug was well-tolerated, although treated patients lost more weight on average than those in the placebo group. Exenatide levels in CSF were about 2 percent of serum levels. Secondary outcomes related to cognition, or quality of life, showed no benefit. A post hoc analysis claimed some potential advantage in mood and well-being subdomains of the assessments (Athauda et al., 2018). Analysis of insulin signaling markers in neuronally-derived blood exosomes confirmed target engagement of brain insulin pathways (Athauda et al., 2019).

From 2016 through 2019, the University of Parma, Italy, ran a trial comparing a 36-week course of once-weekly subcutaneous injection of 2 mg long-acting exenatide to placebo for its effect on cognitive decline in 40 prediabetic patients; the primary outcome was decline on the ADAD-cog.

In June 2018, a Phase 1 open-label study sponsored by the University of Florida started recruiting what was to be 20 participants with Parkinson's to evaluate a one-year course of 2 mg subcutaneous exenatide. The outcomes were imaging measures of free water in the substantia nigra and blood oxygenation in multiple brain regions. This trial stopped enrolling after five patients, and completed treatment in October 2020.

From 2010 to November 2016, the NIA ran a single-center Phase 2 Alzheimer's disease trial. The study compared 5 or 10 micrograms exendin-4 or placebo, taken twice daily for 18 months, in people with a clinical diagnosis of prodromal or mild Alzheimer's disease ascertained by cerebrospinal fluid Aβ42 of below 192 pg/ml, indicating amyloid buildup in the brain. The trial originally aimed to enroll 230 participants and was to run until January 2013, but randomized only 27 participants. After AstraZeneca withdrew its support, it was terminated in November 2016 with 18 participants remaining. Findings have not been published in a peer-reviewed journal, but study results posted on clinicaltrials.gov indicate more cases of nausea in the drug than placebo group, and no statistically significant treatment benefit.

In January 2020, a trial in Stockholm began enrolling 60 people with Parkinson's disease to receive 2 mg once weekly for 18 months, with a primary outcome of changes in brain glucose uptake on FDG-PET. As of September 2022, this trial was listed as fully recruited and active, and was to be completed in October 2023.

In 2020, four new efficacy trials began. In January, University College London began a Phase 3 trial in 200 people with Parkinson's, who will receive 2 mg extended-release exenatide once weekly for two years. The protocol has been published (Vijiaratnam et al., 2021); the trial will finish in mid-2024. In September, another trial at UCL began enrolling 50 people with multiple system atrophy for a 12-month course of once-weekly exenatide. This study was anticipated to be completed in 2022. In February, a multicenter trial in Korea started enrolling 99 people with early PD to test PT320, an extended-release form of exendin-4 that is claimed to have better blood-brain barrier penetration (Li et al., 2019). This trial will compare PT320 to placebo, given by subcutaneous injection once per week for 48 weeks. The current status of this trial is unknown. In preclinical studies in PD mouse models, PT320 was reported to delay dopamine neuron degeneration, disease progression, and lessen L-DOPA-induced dyskinesias (Yu et al., 2020; Wang et al., 2021; Kuo et al., 2023; Wang et al., 2024).

Also in February, a multicenter trial in the U.S. began comparing placebo to two doses of NLY01, Neuraly’s pegylated formulation of exendin-4, in 240 people with early PD. In preclinical pharmacokinetic studies, NLY01 did not enter the brain (Lv et al., 2021). The trial finished in March 2023, after 36 weeks treatment. According to published results, 2.5 or 5 mg NLY01 failed to change the primary endpoint of the MDS-UPRDS parts II and III, compared to placebo (McGarry et al., 2024). Younger patients showed a possible benefit on motor symptoms.

Exendin-4 is also being evaluated in stroke, and brain and spinal cord injury.

For a review of exenatide’s development for Parkinson’s and Alzheimer’s, see Hölscher, 2024.

For details on trials of exendin-4 in neurodegenerative diseases, see clinicaltrials.gov.

Last Updated: 14 May 2024

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Therapeutics

Deep Brain Stimulation-fornix

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Overview

Name: Deep Brain Stimulation-fornix
Synonyms: DBS-f
Therapy Type: Procedural Intervention
Target Type: Unknown
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 3)
Company: Functional Neuromodulation Ltd

Background

Deep Brain Stimulation (DBS) is an invasive treatment where pairs of electrodes are surgically implanted in the brain, and connected to a pulse generator placed under the skin on the chest. DBS-fornix places electrodes in the fiber tract that connects the hippocampus to other parts of the limbic system, and is intended to modulate or ease dysfunction of memory circuits in the brain. A large body of evidence links fornix pathology, amnestic mild cognitive impairment, and the development of Alzheimer’s dementia (reviewed in Benear et al., 2020).

The memory-enhancing effects of fornix stimulation were observed incidentally in a patient undergoing DBS to treat obesity at Toronto Western Hospital in Canada (Hamani et al., 2008). Instead of affecting appetite, the stimulation induced a flashback to a decades-old memory during surgery, and improvement in verbal and spatial memory assessments afterwards. After this, the Toronto investigator founded Functional Neuromodulation to pursue DBS-fornix (DBS-f) as a potential treatment for AD (for rationale, see Mirzadeh et al., 2015). This study, and other single-case reports, have been criticized as potentially misleading (Jun 2010 news).

Several preclinical studies documented improved memory after DBS-f stimulation in rats (e.g., Hescham et al., 2012; reviewed in Senova et al., 2020). In rats, one hour of fornix stimulation elevated markers of neuronal activity, trophic factor expression, and synaptic markers in the hippocampus (Gondard et al., 2015). Multiple labs have reported that DBS-f improves cognition in rat and mouse models of AD (e.g., Leplus et al., 2019; Gallino et al., 2019; Zhang et al., 2015).

Findings

In March 2007-June 2010, an open-label pilot study of bilateral DBS-f ran at the Toronto Western Hospital. Six volunteers with clinically diagnosed probable AD had electrodes implanted and received continuous stimulation for one year. Results were published after peer review (Laxton et al., 2010). The treatment was safe, with no serious adverse effects. Stimulation led to increased glucose uptake in temporal and parietal brain regions, suggesting successful modulation of brain activity. Cognitive testing indicated possible improvements, although there was no placebo control in this open-label study. Additional analyses found enhancements in functional connectivity that correlated with clinical improvement (Smith et al., 2012). Three of the six patients showed a preservation or increase in bilateral hippocampal volume, and the group averaged slower hippocampal volume loss than age-, sex-, and severity-matched AD patients not receiving DBS (Sankar et al., 2015).

In May 2012, the placebo-controlled ADvance DBS-f study began to evaluate the safety, efficacy, and tolerability of the procedure in patients clinically diagnosed mild AD. Participants were allowed to be on acetylcholinesterase inhibitors, but could not change regimens during the study. In this study, all 42 participants had a Medtronics neurostimulator surgically implanted, but only half had the stimulator turned on. Outcomes were acute safety 30 days after surgery, and long-term safety one year later, with secondary outcomes of the ADAS-Cog13 and CDR-SB. Results of the study, at seven locations in the U.S. and Canada, were first reported at the CTAD conference in November 2015 (Nov 2015 conference news) and subsequently published after peer review (Lozano et al., 2016; Ponce et al., 2015). Five patients experienced serious adverse events due to surgery. Two had infection that necessitated lead removal, one needed surgery to reposition leads, and one needed surgery for chronic subdural bleeding. No patients developed neurological issues due to surgery, and adverse events were similar between the ON and OFF groups after lead activation. After one year, there was no difference in cognition between the ON and OFF groups. At six months, the ON group showed increased brain glucose uptake, but the difference was not significant at one year. In a post hoc analysis, patients older than 65 in the ON group trended to improvement in glucose metabolism and cognition, while patients younger than 65 trended to worse cognition with DBS ON (see also Targum et al., 2021).

One year after surgery, everyone had the stimulator turned on in an open-label extension. The treatment continued to be safe and well-tolerated, but did not change clinical trajectory (Leoutsakos et al., 2018).

In this study, about half of patients reported spontaneous, vivid memory flashbacks during initial programming of the stimulator, and some memories became more detailed as the voltage was increased (Deeb et al., 2019). Trial data was used to identify the brain regions and circuits responsible for these flashbacks (Germann et al., 2021), and for eliciting side effects including rapid heart rate, warmth, flushing, and high blood pressure (Neudorfer et al., 2021).

An analysis of electrode placement versus clinical outcomes identified a “sweet spot” in the fornix, at the interface between the circuit of Papez and stria terminalis, where stimulation was significantly associated with cognitive improvement (Rios et al., 2022).

A report has been published on potential brain damage due to DBS-f lead placement (McMullen et al., 2015).

In December 2014, a one-year biomarker and dose-finding study began at the University of Toronto, assessing clinical and imaging outcomes in 12 patients with mild Alzheimer’s dementia. After implantation of the DBS device, the participants receive personalized fornix stimulation, optimized by cognitive testing. Primary outcomes are the ADAS-Cog, CDR, amyloid PET, CSF Aβ and tau, and MRI. Secondary and other outcomes include activities of daily living, verbal and visual memory tests, neuropsychiatric symptoms, and measures of depression, suicidality, and mania. The study is to finish in December 2023.

In August 2019, Functional Neuromodulation began the ADvance II study for U.S. regulatory approval. The 210 participants must be at least 65 years old with CSF biomarker-confirmed AD and mild dementia. They can be taking acetylcholinesterase inhibitors or not, but may not change their regimen during the one-year study. All participants will have the Boston Scientific Vercise™ Directional DBS System surgically implanted, and then be randomized to low- or high-frequency stimulation, or no stimulation. A three-year open label extension is planned. The primary outcome is a composite of scores from ADAS-COG and ADCS-ADL. CDR-SB serves as a secondary outcome. The study is ongoing at 23 locations in the U.S., Canada, and Germany, with primary completion expected in October 2027.

In December 2017, the Beijing Pins Medical Company began testing their implantable neurostimulator for DBS of the fornix or the nucleus basalis of Meynert. The latter is the major source of acetylcholine in the brain, and degenerates early in AD. The study, at one hospital in Beijing, is enrolling 30 participants with amyloid-PET-confirmed AD, a clinical dementia rating of 1.0 or 2.0, and on stable donepezil. Stimulator ON and OFF groups will be compared against a primary outcome of ADAS-COG13. The study was to be completed in December 2020, but its status is unknown. A pilot study of 1.5 to three months of DBS-f with this device in five patients in China produced varying results. Several improved their mood and social function, while one got worse (Mao et al., 2018).

Two small academic trials have reported difficulty recruiting for DBS-f trials. In an open-label trial planned for five patients in France, 110 patients were screened, nine were eligible, two gave consent, and only one underwent surgery (Fontaine et al., 2013). A small study planned for six patients in Spain ultimately published a single-patient case report claiming cognitive stabilization over two years stimulation (Barcia et al., 2022).

A meta-analysis of trials of DBS-f involving a total of 53 people with AD found no evidence for improved cognition (Majdi et al., 2023). Besides the small number of participants, the studies differed in their stimulation parameters, and the authors cite the need for larger, standardized trials.

DBS-f is being tested for additional indications. A Mayo Clinic study is testing dual stimulation of the subthalamic nucleus and fornix/hypothalamus to improve cognitive function in people with Parkinson’s disease. Beginning in April 2012, the open-label study is enrolling 12 participants, and plans to finish in January 2025. Acute DBS-f also has been reported to improve memory and reduce the risk of seizure in people with temporal lobe epilepsy (Koubeissi et al., 2013; Koubeissi et al., 2022).

Other studies evaluating DBS for AD are targeting the nucleus basalis of Meynert (e.g., Hardenacke et al., 2016), and the ventral capsule/ventral striatum, a modulator of frontal lobe networks (Scharre et al., 2018).

For details on DBS-f trials, see clinicaltrials.gov.

Last Updated: 07 Nov 2023

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Overview

Name: Ladostigil
Synonyms: Ladostigil hemitartrate, TV3326
Therapy Type: Small Molecule (timeline)
Target Type: Cholinergic System (timeline)
Condition(s): Mild Cognitive Impairment, Alzheimer's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Alzheimer's Disease (Discontinued)
Company: Avraham Pharmaceuticals Ltd

Background

Ladostigil is a multimodal, or multifunctional, (MFC) compound that combines two pharmacophores taken from rivastigmine and rasagiline. This "dirty" drug has been reported to be an inhibitor of the enzymes acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B, and to have neuroprotective and antidepressant effects (Weinreb et al. 2008; Youdim 2013; Bansal and Silakari 2014).

Avraham Pharma developed this compound initially for Alzheimer’s disease but later changed to an indication of mild cognitive impairment (MCI).

Findings

In 2011 and 2012, Avraham Pharmaceuticals evaluated a six-month course of escalating doses of up to 80 mg twice daily of ladostigil in a Phase 2 study of 201 people with mild to moderate Alzheimer's disease. Conducted in five European countries, this trial missed its primary endpoint of change on the ADAS-cog11, and development for Alzheimer's disease was terminated (see company press release).

In January 2012, the company started a second Phase 2 study, this time evaluating a lower dose for its ability to delay progression from MCI to AD. Conducted in Austria, Germany, and Israel, this trial enrolled 210 people with a clinical diagnosis of MCI. It compared a three-year course of 10 mg of ladostigil once daily to placebo on the primary outcome of conversion from MCI to AD as determined by a clinical dementia rating (CDR) of 1 or greater. In September 2016, the company disclosed that ladostigil missed its primary endpoint in this trial, as well, but trended in the direction of a treatment benefit. Treatment benefits were reported on MRI and select cognitive tests (see company website). Results were formally published in Neurology (Schneider et al., 2019).

Last Updated: 13 Sep 2019

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Overview

Name: Masitinib
Synonyms: Masivet, Kinavet, AB1010, Masitinib mesylate
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 3), Amyotrophic Lateral Sclerosis (Phase 3)
Company: AB Science

Background

Masitinib is an orally available inhibitor of the protein tyrosine kinase c-kit, which is expressed on cancer cells. Masitinib also inhibits PDGF and FGF receptors, and fyn and lyn kinases (Dubreuil et al., 2009). Masitinib interferes with the survival, migration, and activity of mast cells, and in this role has attracted attention for the treatment of neuroinflammatory and neurodegenerative disorders. Also relevant to Alzheimer’s, AB Science claims masitinib modulates microglia through inhibition of the macrophage colony stimulating factor receptor 1 kinase.

In preclinical work, chronic treatment with masitinib was reported to restore spatial learning and synaptic density in the hippocampus in the APP/PS1 mouse model of amyloidosis (Li et al., 2020).

Findings

From 2006 to 2009, AB Science conducted a Phase 2 trial comparing 3 and 6 mg/kg/day of masitinib or placebo, taken twice daily for six months as an add-on therapy to cholinesterase inhibitor and/or memantine treatment. Conducted at 12 centers in France, this trial enrolled 34 patients with mild to moderate Alzheimer's disease and used change in cognition as measured by the ADAS-cog as primary outcome. Masitinib was reported to have reduced cognitive decline in this study, with a claimed effect size of 6.8 and 7.6 at three and six months, respectively. Side effects including gastrointestinal disorders, edema, and rash occurred about twice as often with masitinib than placebo. Nineteen of 34 participants in the masitinib group withdrew before the study completed, compared with two of the eight placebo participants. Seven of the 19 withdrawals were reported as due to treatment-related adverse effects. The drug's tolerance was called acceptable in this report (Piette et al., 2011).

In 2012, a Phase 2b/3 trial began. Conducted in six European countries, it was to enroll 396 patients with mild to moderate Alzheimer's, comparing six months of 3 or 4.5 mg/kg daily, or placebo, as an add-on to cholinesterase and memantine treatment. In 2018, the study was enlarged to enroll 721 people from 118 sites in 21 mainly European countries, and added a dose escalation group receiving 4.5 mg/kg daily for three months, then 6 mg/kg, with a matching placebo group. The 3. 5 mg/kg group was discontinued. Cognition as measured by ADAS-cog and global function as measured by the ADCS-ADL were co-primary outcome measures.

In late 2020, the company announced that the study met its primary goal (Dec 2020 news). The 4.5 mg/kg treatment group improved on ADAS-cog and ADCS-ADL, while the placebo group declined. The ADAS-cog met the preset statistical threshold for success of p<0.025. Fewer drug- than placebo-treated participants progressed to severe dementia. No treatment effect was seen in the titration arm. Serious adverse events were twice as frequent in treated groups than placebo.

Masitinib was evaluated in Spain for amyotrophic lateral sclerosis as an add-on therapy to riluzole. This trial started in January 2013 as a Phase 2 with 45 patients but later was expanded into a Phase 3 study with 394 patients (see clinicaltrials.gov). The company reported that 48 weeks of 4.5 mg/kg/day slowed loss of motor abilities, except in patients with rapid progression (May 2017 news; Mora et al., 2019). Patients in the trial were eligible to continue masitinib. After six years, masitinib extended survival by two years in the subset of patients with mild symptoms at the start of treatment and who were not fast progressors (Mora et al., 2021). It did not affect survival in the overall study population. In October 2020, a confirmatory Phase 3 study began evaluating 48 weeks of 4.5 and 6 mg/kg or placebo in 495 participants with mild to moderate symptoms. It will run through 2022.

On June 1, 2021, AB Science announced a voluntary pause in recruitment and randomization for ongoing masitinib studies, including the ALS trial. Analysis of pooled results from unblinded, controlled trials identified a potential risk of ischemic heart disease that needs further investigation, the company said (see details). Dosing will continue for those already on treatment.

AB Science is also developing masitinib for multiple sclerosis, where it was reported to slow disease progression in a Phase 3 trial (2020 abstract). Clinical development for pancreatic cancer, asthma, mastocytosis, and COVID-19 disease is ongoing, as well. Masitinib has been tested in clinical trials for breast, colorectal, gastric, head and neck, liver, lung, and esophageal cancer, as well as glioblastoma, metastatic melanoma, multiple myeloma, and T cell lymphoma. The drug is available to treat cancer in veterinary medicine under the names Masivet or Kinavet.

For all trials of masitinib in Alzheimer's, see clinicaltrials.gov.

Clinical Trial Timeline

Phase 2
Phase 3
Study completed / Planned end date
Planned end date unavailable
Study aborted

Sponsor	Clinical Trial	2004	2005	2006	2007	2008	2009	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020	2021	2022	2023	2024	2025	2026	2027	2028	2029	2030	2031	2032	2033	2034
AB Science	NCT00976118	N=34
AB Science	NCT01872598	N=396

Last Updated: 22 Jul 2021

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Overview

Name: Gantenerumab
Synonyms: RO4909832, RG1450, R1450
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Chugai Pharmaceutical Co., Ltd., Hoffmann-La Roche

Background

Gantenerumab is a fully human IgG1 antibody designed to bind with subnanomolar affinity to a conformational epitope on Aβ fibrils. It encompasses both N-terminal and central amino acids of Aβ. The therapeutic rationale for this antibody is that it acts centrally to disassemble and degrade amyloid plaques by recruiting microglia and activating phagocytosis. Gantenerumab preferentially interacts with aggregated brain Aβ, both parenchymal and vascular. It binds to cerebral amyloid angiopathy fibrils more avidly than some other Aβ antibodies (Soderberg et al., 2024). The antibody elicits phagocytosis of human Aβ deposits in AD brain slices co-cultured with human macrophages. It also neutralizes oligomeric Aβ42-mediated inhibitory effects on long-term potentiation in rat brains. In APP/PS-1 transgenic mice, gantenerumab binds to cerebral Aβ, reduces small plaques by recruiting microglia, and prevents new plaque formation. Gantenerumab does not alter plasma Aβ (Bohrmann et al., 2012). It has been studied as a potential combination therapy with the Roche BACE inhibitor RG7129 in mouse models of Aβ amyloidosis (Apr 2013 conference news).

Findings

Four Phase 1 trials conducted internationally in a total of 308 patients have tested the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of infused and subcutaneous gantenerumab in healthy controls and people with Alzheimer's disease, respectively. Gantenerumab was generally safe and well-tolerated, but amyloid-related imaging abnormalities (ARIA) are a concern. For example, in one published study, two of six patients in the highest-dose group had focal areas of inflammation or vasogenic edema on MRI scans in brain areas with the most amyloid reduction (Ostrowitzki et al., 2012). The imaging finding was transient, but ARIA are being monitored closely with MRI in subsequent trials. One dosing study with 16 participants indicated an 11 percent difference in the amount of amyloid change between placebo and the higher dose at six months.

In 2010, Roche started a Phase 2 trial of 105 or 225 mg gantenerumab injected subcutaneously once a month into 360 participants, and in 2012 expanded the study to a Phase 2/3 registration trial of 799 people. Called SCarlet RoAD, this multinational, 159-center study of gantenerumab's effect on cognition and function in prodromal Alzheimer's disease delivered treatment for two years with the option of a two-year extension. Co-primary endpoints were to be the Clinical Dementia Rating Sum of Boxes (CDR-SOB) and change in brain amyloid levels as measured by PET. The latter was dropped mid-study, and instead the trial included a PET sub-study of 90 participants. SCarlet RoAD enrolled people aged 50 and older whose memory function tested below normal on the Free and Cued Selective Reminding Test (FCSRT-IR), whose MMSE was 24 or above, whose CDR was 0.5, and who were positive on amyloid PET. This was one of first times the new diagnostic criteria by the International Working Group were applied in a large clinical trial. At the November 2014 CTAD conference, data were reported to suggest that this screening process worked to enroll a homogenous population of early symptomatic patients whose memory deficit was likely due to underlying Alzheimer's pathology (Dec 2014 conference news).

On December 19, 2014, Roche stopped dosing in SCarlet RoAD based on an interim futility analysis (Dec 2014 news). In July 2015, Roche reported no efficacy on primary or secondary endpoints in this trial, but a trend toward a benefit in the fastest progressors based on post hoc analysis (Aug 2015 conference news). Subsequent reports noted biomarker and efficacy signals on the high dose among fast progressors, and the data was formally published (Nov 2015 conference news; Ostrowitzki et al., 2017). SCarlet RoAD participants who entered the open-label extension study were titrated up to 1,200 mg subcutaneous gantenerumab. The slower this titration, the less ARIA-E they experienced (Dec 2017 conference news). The open-label extension was completed in September 2020.

In March 2014, Roche started a Phase 3 trial of monthly subcutaneous injections of gantenerumab in what was anticipated to be 1,000 patients with clinical diagnoses of mild AD. This trial, called Marguerite RoAD, used the ADAS-Cog and ADCD-ADL as co-primary and various biomarkers and clinical/neuropsychiatric measures as secondary outcomes. On October 10, 2016, the clinicaltrials.gov entry for this study was updated to reflect that this trial had stopped enrolling at 389 participants. Roche later reported that, like SCarlet RoAD, Marguerite RoAD had failed an interim futility analysis. It was switched to an open-label extension study, with participants titrated up to 1,200 mg gantenerumab.

At the 2018 AAIC, Roche reported that two years of high-dose gantenerumab in the SCarlet and Marguerite RoAD extension studies lowered brain amyloid by an average of 59 centiloid on florbetapir PET, with half of the 28 participants who reached this timepoint falling below the threshold for amyloid positivity, and the rest on trajectory to do so. About one-third of participants in the extension studies developed ARIA-E; the majority were asymptomatic (Aug 2018 conference news; Klein et al., 2019). In a subsequent paper, the company reported continued amyloid reductions in the third year of the extension. Of 30 participants with three-year PET scans, 80 percent reduced their amyloid load below the positivity threshold (Klein et al., 2021). At the 2022 AAIC, biomarker data was presented. Consistent with other trials (see DIAN-TU results below), treatment increased plasma Aβ40 and Aβ42, and decreased p-tau217 and p-tau181. Compared to historical controls, the OLE cohort declined more slowly on the CSDR-SB, ADAS-Cog13, and MMSE (Aug 2022 conference news).

Gantenerumab, in parallel with Eli Lilly's solanezumab, was evaluated by the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) in a Phase 2/3 trial aimed at preventing dementia in 210 people who are on the path to Alzheimer’s disease due to an inherited autosomal-dominant mutation in APP, presenilin-1, or presenilin-2. This trial began in December 2012 as a two-year, Phase 2 biomarker study (Oct 2012 news). It later converted into a Phase 3 registration trial with a cognitive endpoint measured after four years of treatment. Gantenerumab dosing was increased fivefold, from 225 mg to 1,200 mg monthly, midway through the trial. This trial, completed in November 2019, missed its primary endpoint. Gantenerumab produced no significant treatment-related change on the DIAN Multivariate Cognitive Endpoint, a composite developed for this trial (Feb 2020 news).

Additional data were presented at the 2020 AAT-AD/PD Focus Meeting. Of 194 participants, 52 received gantenerumab and 39 completed the trial. Gantenerumab treatment led to a large reduction in amyloid plaque as per PiB PET scans, and it normalized CSF Aβ42. Gantenerumab reduced toward normal elevated levels of CSF total tau and p-tau181, and slowed the rise of CSF neurofilament light (Apr 2020 conference news; Apr 2020 conference news). Analysis of the cognitive data revealed that people who were symptomatic at baseline declined over the course of the study, while those who were asymptomatic remained stable. This dichotomy lessened the power of the study to detect treatment effects. Peer-reviewed results were published (Jun 2021 news; Salloway et al., 2021, Joseph-Mathurin et al., 2022; Wang et al., 2022). In a subsequent biomarker analysis, treatment improved markers of synaptic function and inflammation, with greater benefits observed in presymptomatic participants (Wagemann et al., 2024).

Based on the biomarker data, DIAN-TU and Roche invited participants from all arms of this trial to an open-label extension with high-dose gantenerumab (1,200 mg monthly) for up to three years. The dose was further increased to 3,000 mg monthly for the last two years. This OLE started in the fall of 2020, and finished in August 2023. According to preliminary results presented at CTAD that year, asymptomatic mutation carriers who took gantenerumab for eight years were half as likely to progress to symptoms, or developed symptoms six years later than their expected age of onset (Nov 2023 conference news). More data was presented at the 2024 AAIC, comparing 22 initially asymptomatic mutation carriers to 74 untreated people. In some participants, gantenerumab treatment slowed or stopped tau tangle accumulation; in others, it improved mild memory symptoms. A few participants remained cognitively normal up to 10 years after their expected age of onset (Aug 2024 conference news; Aug 2024 conference news). Despite the use of high doses, ARIA incidence was similar to other trials (Aug 2024 conference news).

In 2016, Roche started two new Phase 1 trials, both investigating subcutaneous administration of higher doses of gantenerumab, in a total of 98 healthy participants. According to published results, the procedure was safe and injection pain tolerable, opening the possibility of at-home administration (Portron et al., 2020).

On March 6, 2017, MorphoSys, which partners in the development of gantenerumab, announced Roche would start two new Phase 3 trials for prodromal or mild, amyloid-confirmed AD. Graduate 1 and 2 began enrolling in June 2018, each at 216 different sites worldwide, with a goal of 760 participants each. Participants were titrated up to 1,020 mg subcutaneous gantenerumab, given as 510 mg every two weeks, or placebo and treated for two years, with an option to continue on open-label. The primary outcome measure was change on the CDR-SB. In March 2020, target enrollment for each trial was increased to 1,016. According to baseline data presented at the November 2021 CTAD, enrollment was complete at 1,966, with data readout expected in late 2022 (conference news).

At the 2019 AD/PD conference in Lisbon, Portugal, Roche showed further analyses of the two-year open-label extension of the SCarlet and Marguerite RoAD studies. It indicated that ARIA tends to occur in hotspots of rapid amyloid removal, but is not required for amyloid clearance across the brain. Roche also showed how comparing titration schemes in the combined open-label study informed the Graduate trial design of a single uptitration scheme independent of participants' ApoE genotype (May 2019 news).

In May 2020, the company began a second open-label continuation for participants in the Scarlet and Marguerite RoAD studies. The 116 participants receive antibody every four weeks, at the dose they were on previously. At the same time, Roche registered a rollover study for people who completed either the double-blind or open-label phases of Graduate 1 and 2. In this open-label continuation, an expected 2,032 participants will receive 510 mg of gantenerumab every two weeks. The trial started enrolling in February 2021 and was to run through 2024.

In November 2020, Roche began a Phase 2 trial testing once-weekly subcutaneous gantenerumab injections in 192 people with prodromal to mild AD. Starting with monthly shots of 120 mg, participants in this two-year study ramped up to a target dose of 255 mg weekly. Administration was at home by a care partner or in the doctor’s office by a health care professional. The primary endpoint was change in amyloid deposition from baseline; secondary outcomes included safety, pharmacokinetics, and participant experience with home injection. Roche ended the trial in January 2023, when the company discontinued development of gantenerumab. At that time, 149 patients had one year PET data; 12 had two-year scans. According to published results, amyloid reduction averaged 26 and 35 centiloids after one or two years, respectively. Most care partners found home administration easy and convenient, and no new safety issues were identified (Boess et al., 2024).

In October 2021, the FDA designated subcutaneous gantenerumab a Breakthrough Therapy, offering an accelerated review and approval process.

In March 2022, Roche began SKYLINE, a Phase 3 secondary prevention trial to evaluate gantenerumab in cognitively unimpaired people with CSF or PET evidence of brain amyloid. It was to enroll 1,200 participants between 60 and 80 years old, and test four years of gantenerumab or placebo against a primary outcome of the Preclinical Alzheimer’s Cognitive Composite-5 (Mar 2022 conference news). Participants were to receive a dose of 255 mg weekly, or 510 mg every other week, and to have the option to self-administer the antibody at home. Secondary outcomes included progress to cognitive impairment, functional measures, structural MRI, blood biomarkers of amyloid, tau, and neurodegeneration, and safety. PET and CSF substudies were planned. Starting in six locations in the U.S., the trial was to run in 17 countries through 2028.

On November 14, 2022, Roche and Genentech announced that gantenerumab failed to slow cognitive decline on the CDR-SB in the Graduate trials (Nov 2022 news). At the December 2022 CTAD conference, Roche presented more results on the trial, which enrolled 1,965 participants from 30 countries (Dec 2022 conference news). The data were subsequently published (Bateman et al., 2023). Gantenerumab cleared only half as much plaque as expected, and fewer participants became amyloid-negative on PET scans than in previous trials. Clinical measures trended to improvement, but fell short of statistical significance. People who cleared amyloid below the positivity threshold did the best clinically. Biomarkers of tau, synaptic loss and neuronal death dropped or slowed their increase significantly on antibody compared to placebo. The company announced it had stopped all gantenerumab trials including SKYLINE, but said it would continue to provide antibody for the ongoing DIAN-TU open-label extension study. For a review of gantenerumab's development history, see Bateman et al., 2022.

In December 2021, DIAN-TU investigators had launched a primary prevention trial testing gantenerumab in people as young as 18 with familial AD mutations but no or little brain amyloid. The study plans to enroll approximately 220 participants for four years and measure amyloid accumulation. An open-label extension will run for an additional four years, with a primary endpoint of odds of lower disease progression based on modeling of the change in six CSF and MRI biomarkers, compared to an observational control group and the placebo group from the previous gantenerumab study. After Roche stopped gantenerumab development, DIAN-TU investigators announced that they will choose a different drug for this trial (20 Dec 2022 release). In May 2024, the trial was relaunched with remternetug (press release).

Roche is developing a new formulation of gantenerumab that uses “brain shuttle” technology to increase the antibody’s ability to enter the brain (RO7126209).

New analyses using gantenerumab trial data continue to be published, for example to develop quantitative disease models, validate ARIA rating scales, to compare radiotracer response in drug trials, and to develop new bioassays (Mazer et al., 2022; Bracoud et al., 2023; Chen et al., 2023; Wang et al., 2023). DIAN-TU data was used to validate amyloid reduction as a surrogate endpoint for clinical improvement (Wang et al., 2024).

For all gantenerumab trials, see clinicaltrials.gov.

Clinical Trial Timeline

Phase 2
Phase 2/3
Phase 3
Study completed / Planned end date
Planned end date unavailable
Study aborted

Sponsor	Clinical Trial	2008
Hoffmann-La Roche	NCT01224106	N=799
Washington University School of Medicine	NCT01760005	N=490
Washington University School of Medicine	NCT04623242	N=194RESULTS
Hoffmann-La Roche	NCT02051608	N=389
Hoffmann-La Roche	NCT03444870	N=1016
Hoffmann-La Roche	NCT03443973	N=981
Hoffmann-La Roche	NCT04339413	N=116
Hoffmann-La Roche	NCT04592341	N=150
Hoffmann-La Roche	NCT04374253	N=2032

Last Updated: 23 Sep 2024

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Overview

Name: Leqembi
Synonyms: Lecanemab-irmb, BAN2401, mAb158
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Approved)
Company: BioArctic AB, Biogen, Eisai Co., Ltd.

Background

BAN2401 is the humanized IgG1 version of the mouse monoclonal antibody mAb158, which selectively binds to large, soluble Aβ protofibrils. This therapeutic antibody grew out of the discovery of the “Arctic” mutation in APP, which leads to a form of clinically typical Alzheimer's disease that is marked by particularly high levels of Aβ protofibrils and relative absence of amyloid plaques (see Nilsberth et al., 2001). mAb158 was originally developed at Uppsala University, Sweden (Englund et al., 2007).

In its preclinical development, mAb158 was found to reduce Aβ protofibrils in brain and CSF of Tg-ArcSwe mice (Lord et al., 2009; Tucker et al., 2015). Subsequent studies in mouse neuron-glial co-cultures showed that mAb158 may protect neurons, i.e., reduce Aβ protofibril toxicity, by counteracting the pathological accumulation of these protofibrils in astrocytes (Söllvander et al., 2018). In a direct comparison with the anti-amyloid antibodies aducanumab and gantenerumab, lecanemab was reported to bind most strongly to Aβ protofibrils, while the others preferred more highly aggregated forms (Nov 2021 conference news). Lecanemab was shown to bind to diffusible Aβ fibrils and protofibrils from human brain tissue (Nov 2022 news; Johannesson et al., 2024). It bound to cerebral amyloid angiopathy fibrils less avidly than other Aβ antibodies (Soderberg et al., 2024). In aged Tg2576 mice, mAb158 lowered Aβ protofibrils within four weeks, and later reduced Aβ plaques; both effects reversed after treatment was stopped (Rizoska et al., 2024). Lecanemab was also reported to interfere with the binding of Aβ protofibrils to fibrinogen, which may offer additional protection against clotting abnormalities and synaptotoxicity that occur in AD (Singh et al., 2024).

BAN2401 was licensed to Eisai, which in March 2014 signed a collaboration agreement with Biogen for joint development of this therapeutic antibody.

While clinical trials are being conducted in Alzheimer's (see below), preclinical research with postmortem Down's syndrome brain sections indicates binding of lecanemab to Aβ deposits in this disease, as well (Johannesson et al., 2021). In another study of postmortem tissue from 15 people with DS, lecanemab bound extensively to both amyloid plaques and vascular amyloid (Liu et al., 2024).

A hexavalent antibody based on mAb158 is being developed, with the goal of enhancing binding strength selectively to Aβ protofibrils (Rofo et al., 2021).

Findings

A multicenter Phase 1 trial tested the safety, tolerability, and pharmacokinetics of single and multiple ascending intravenous doses of BAN2401 in 80 people with mild to moderate AD. Changes in Aβ levels were also measured. BAN2401 was well-tolerated at all doses tested, up to 10 mg/kg every two weeks for four months, with amyloid-related imaging abnormalities (ARIA-E, ARIA-H) occurring at the same rate in both placebo and BAN2401. The antibody entered the CSF and showed dose-dependent exposure, though with a short serum elimination half-life of seven days and no clear effect on CSF biomarkers. Results were published (Logovinsky et al., 2016).

Subsequently, a Phase 2, 18-month U.S. trial tested five different intravenous doses of BAN2401 in a Bayesian adaptive design. Allocation of subsequent enrollees to different groups was adjusted in response to frequent interim analyses, the first to be done in late 2015 after the first 196 patients had entered the trial, and again every time 50 more people had enrolled (for detailed description of this innovative trial design see Satlin et al., 2016). This trial enrolled 856 people who had either early stage AD as defined by the proposed NIA-AA diagnostic criteria or mild cognitive impairment due to AD, or who met NIA-AA criteria for probable AD and whose diagnosis was confirmed by a positive amyloid PET scan. As primary outcomes, the trial measured 12-month change from baseline in the new ADCOMS composite of cognitive tests (Wang et al., 2016), and safety.

In 2017 the sponsors announced that BAN2401 had shown no cognitive benefit at this 12-month time point. However, futility conditions had not been met either at the 17 interim analyses conducted until then. Therefore the trial continued to full enrollment of 856 participants, and out to the full treatment period of 18 months (Dec 2017 news). In February 2018, the trial protocol was amended to offer up to five years of additional treatment in an open-label extension phase, in which change on the ADCOMS will be measured at each visit.

The sponsors announced top-line results of the blinded 18-month treatment phase in July 2018 (see July 2018 news). The highest antibody dose of twice-monthly 10 mg/kg slowed progression on the ADCOMS and reduced brain amyloid accumulation, according to a press release from BioArctic. Full results of this Phase 2b study were presented at AAIC (Jul 2018 news). The antibody reduced brain amyloid by up to 93 percent in the highest-dose group. This dose slowed cognitive decline by 47 percent on the ADAS-Cog, and by 30 percent on the ADCOMS. The next-lower dose, 10 mg/kg monthly, showed a trend toward slower cognitive decline that was not statistically significant. In an analysis of CSF from a subgroup of patients, the treatment caused a dose-dependent rise in CSF Aβ42. MRI scans detected ARIA in just under 10 percent of participants overall, and in fewer than 15 percent of those with ApoE4 in the highest-dose group. Most ARIA occurrences were asymptomatic.

The results were complicated by uneven distribution of ApoE4 carriers between placebo and treatment groups, which was caused by an EMA request during the trial. A subgroup analysis, presented at CTAD, suggested that the treatment benefit was not due to this imbalance (Nov 2018 conference news). Full results were subsequently published (Swanson et al., 2021). Additional analysis of the three cognitive endpoints with six different statistical methods found a consistent positive effect of treatment (Nov 2021 conference news).

An open-label extension to this trial re-enrolled its participants to deliver the highest antibody dose for up to two years total. As reported at AD/PD 2019 in Lisbon, Portugal, Eisai/Biogen planned to treat up to 250 people in this extension, which was to run until August 2021 (May 2019 conference news). Baseline data from 35 participants suggested that brain amyloid load had remained steady during a two-year pause in antibody dosing, but that cognition declined when BAN2401 was discontinued (Dec 2019 conference news). One-year brain imaging data from 76 participants, presented in December 2020 at CTAD, indicated that people previously treated with placebo had large decreases in their brain amyloid since entering the OLE, while those previously treated with antibody maintained low levels of brain amyloid. ARIA-E incidence was comparable to the core study. Most ARIA-E was asymptomatic and resolved within four to 12 weeks. Continuing to dose people with mild to moderate ARIA-E appeared to pose no additional safety issues (Nov 2020 conference news). More one-year OLE data on 180 participants were presented in March 2021 at AD/PD. Brain amyloid fell fastest in those who began the OLE with the highest amyloid. By the end, 80 percent of participants were judged amyloid-negative, with SUVRs below 1.17 (Mar 2021 conference news).

At the July 2021 AAIC, Eisai reported 18-month OLE data on 100 people. It suggested a slowing of cognitive decline in the open-label phase, compared to ADNI historical data. CSF Aβ42/40, which had increased with treatment during the placebo-controlled phase of the trial, started to decline during the dosing gap, but rose again in all participants after open-label treatment began. A post hoc analysis across the entire study duration suggested cognition declined more slowly in people on lecanemab than in those on placebo (Aug 2021 conference news). More data presented at the Nov 2021 CTAD showed a correlation between plaque clearance and slowed decline on ADCOMs in the OLE (Nov 2021 conference news). At the same conference, Eisai reported that changes in plasma ptau181 tracked with changes in amyloid PET and plasma Aβ42/40. OLE results were formally published (McDade et al., 2022), as were details on ARIA in the completed study (Honig et al., 2023), and an explication of the advantages of the Bayesian design (Berry et al., 2023).

In March 2019, Eisai began a Phase 3 trial called Clarity AD, to be run at 250 sites across the world. It aimed to enroll 1,566 people with early symptomatic AD, who received 10 mg/kg drug or placebo infusion every two weeks for 18 months, followed by a two-year open-label extension. The primary outcome in the core study was change in CDR-SB at 18 months, with secondary outcomes of brain amyloid, ADCOMS, and ADAS-Cog14 subscale. In the extension phase, primary outcomes were change in CDR-SB as well as safety. Change in the CSF biomarkers neurogranin, neurofilament light chain, Aβ(1-42), total tau, and phospho-tau from baseline up to 45 months were originally listed as primary outcomes in the trial registration, but dropped in July 2019. Plasma and CSF biomarkers, as well as amyloid and tau PET, are being assessed in optional longitudinal substudies.

As of October 2020, Clarity AD had randomized 1,222 participants, with demographic and cognitive scores similar to the Phase 2 study (Nov 2020 conference news). By March 2021, it had exceeded its enrollment goal, at 1,794 patients, the company announced (press release). In 2022, the extension added an option for a weekly subcutaneous injection of 720 mg. It is set to run until 2027.

In February 2020, the Alzheimer’s Therapeutic Research Institute announced that the Alzheimer's Clinical Trial Consortium (ACTC) would conduct a large Phase 3 study of lecanemab, called AHEAD 3-45 and co-funded by the NIH and Eisai (press release). It started in July 2020 as a four-year trial that comprises two sub-studies in a combined 1,400 people who are cognitively normal but have elevated brain amyloid. A3 is enrolling 400 people whose amyloid is below the brain-wide threshold for positivity; they will receive 5 mg/kg titrating to 10 mg/kg BAN2401 or placebo every four weeks for 216 weeks, and their primary outcome will be change in brain amyloid PET at that time. A45 is enrolling 1,000 participants who have a positive amyloid PET scan. They will receive BAN2401 titrated to 10 mg/kg every two weeks for 96 weeks, followed by 10 mg/kg every four weeks through week 216. Their primary outcome is change from baseline on their Preclinical Alzheimer Cognitive Composite 5 (PACC5) score, also at week 216. Secondary outcomes for A45 include change in brain amyloid PET and cognitive function. Both studies will measure change in tau PET as a secondary outcome. This new study will use blood Aβ42/40 measures to rule out participants unlikely to have elevated brain amyloid before proceeding to PET imaging (for details, see Rafii et al., 2022).The first person was dosed in this trial in September 2020; as of the July 2021 AAIC, 77 people had been randomized. As of November 2022, 107 sites were recruiting around the world. In early 2024, a two-year open-label extension was added, with trial completion expected in February 2031.

In June 2021, the FDA designated lecanemab a breakthrough therapy, expediting regulatory review, and soon after, Eisai/Biogen began their application for marketing approval (press release; Oct 2021 news). In December 2021, the agency granted fast-track designation (press release).

In September 2021, Eisai began a Phase 1 evaluation of lecanemab subcutaneous administration. The study compared the pharmacokinetics, bioavailability, and safety of a single 700 mg injection under the skin in the abdomen to 10 mg/kg given intravenously in 60 healthy people; it was completed in January 2022. In September 2022, a Phase 1 study started evaluating bioequivalence of a subcutaneous formulation delivered with an auto-injector device; it enrolled 160 healthy participants and finished in January 2023.

In November 2021, the DIAN-TU announced its choice of lecanemab for the first DIAN-TU anti-amyloid/anti-tau concurrent trial (Nov 2021 conference news). It will pair lecanemab with the anti-tau antibody E2814 in the Tau NexGen prevention study in 168 people with familial AD mutations. All will receive lecanemab, while half will get E2814, and half a matching placebo, against a primary outcome of change in tau PET. This trial will run at 40 sites in the Americas, Australia, Japan, and six European countries, until 2027 (Mar 2021 news). As of July 2024, the trial was fully enrolled with 197 participants.

In May 2022, Eisai/Biogen completed lecanemab’s FDA submission, based on the Phase 2 data (May 2022 news). In July 2022, the FDA granted priority review status to the application, with a decision date of January 6, 2023 (Jul 2022 news).

On September 27, 2022, Biogen and Eisai reported positive top-line results on all primary and secondary outcomes of the Phase 3 Clarity AD study (Sep 2022 news). Results were presented in December at the 2022 CTAD conference, and published the same day (Dec 2022 conference news; van Dyck et al., 2023). Lecanemab slowed decline on the CDR-SB by 27 percent compared to placebo at 18 months. Key secondary endpoints, including the ADAS-Cog14, ADCOMS, and ADCS MCI-ADL, all showed a similar slowing of decline. Two-thirds of the treated group became PET-amyloid negative at 18 months. Tau PET indicated a significant slowing of tangle accumulation in the medial temporal lobe, and trended toward slowing in other brain regions. The astrocytosis biomarker GFAP was reduced on treatment, but markers of neurodegeneration were mixed. Safety was in line with past studies, with amyloid-related ARIA-E detected in 12.6 percent of treated participants versus 1.7 percent of the placebo group. About one-quarter had symptoms, which were typically mild and transient. Three people had severe symptoms, but the company did not say what they were. Full safety data were published (Honig et al., 2024).

Three deaths from brain hemorrhage have been reported in the lecanemab open-label extension (Jan 2023 news). Two of the three people had received blood thinners. In Clarity, macrohemorrhages, defined as any brain bleed larger than 1 cm, occurred in 0.6 percent in the treatment group, and 0.1 percent in the placebo group; for people on anticoagulants and lecanemab, this rate increased to 2.4 percent. According to a news article, the third fatality was a 79-year old woman with pre-existing cerebral amyloid angiopathy (Piller, 2023). Published in December 2023, her autopsy report detailed fatal cerebral, Aβ-related arteritis after her third dose of lecanemab (Solopova et al., 2023; Jan 2024 news). A 65-year-old woman who received three doses of lecanemab died after being treated with tissue plasminogen activator for acute stroke symptoms; her brain autopsy revealed inflammation in blood vessels with cerebral amyloid angiopathy. The examination also showed evidence of phagocytic clearance of vascular Aβ and parenchymal Aβ plaques, and other changes suggesting Aβ and tau clearance (Castellani et al., 2023; Reish et al., 2023).

On January 6, 2023, the FDA approved lecanemab under the Accelerated Approval pathway, based on evidence of effect on the surrogate endpoint of amyloid removal in the Phase 2 trial, and a reasonable likelihood of clinical benefit (FDA press release; Jan 2023 news). Lecanemab is sold under the brand name Leqembi.

In March 2023 , the U.S. Veterans Health Administration announced it would cover the cost of lecanemab for veterans in the early stages of AD, excluding those with two copies of APOE4 (press release; VA use criteria).

Additional efficacy data from the Clarity trial, presented at the March 2023 AD/PD conference and subsequently published, showed benefit on self-reported outcomes capturing quality of life and caregiver burden (April 2023 conference news; Cohen et al., 2023).

In March 2023, Leqembi Appropriate Use Recommendations were published (Cummings et al., 2023). They stipulate that it not be prescribed for people taking anticoagulants, or those with a clotting disorder, strokes, or seizures. People on lecanemab should not be treated with acute thrombolytics such as tPA, though common antiplatelet medications such as aspirin or clopidogrel are allowed. The AUR recommend APOE genotyping prior to therapy, so clinicians can discuss risks with patients, but allow treatment for APOE4 homozygotes. A schedule of monitoring MRIs is recommended to include scans at baseline, and before the fifth, seventh, and 14th biweekly infusions. Scans are recommended at one year for APOE4 carriers and people with any ARIA during the first year. By January 2024, approximately 2,000 to 3,000 patients in the U.S. were receiving Leqembi (Jan 2024 news). Extrapolation from Swedish population data indicated that about 5.9 million European and 2.2 million U.S. patients might be eligible for treatment (Dittrich et al., 2024).

In June 2023, Beth Israel Deaconess Medical Center in Boston registered a prospective comparative study of monoclonal antibodies for the treatment of AD. This study creates a patient registry, as required for Medicare coverage of Leqembi or other antibodies once approved (see CMS Decision Summary; Jun 2023 news). The study will enroll up to 500 patients at the hospital’s Cognitive Neurology Unit, and follow them for 30 months to determine if the antibodies slow cognitive and functional decline, to identify associations between patient characteristics and side effects, and to establish the time to clinical benefit. In early 2024, Emory University in Atlanta began enrolling 735 patients for a similar study. In January 2024, Health Partners Institute Neurology Clinic in St. Paul, Minnesota, began a 20-patient study of the feasibility of lecanemab treatment and outcomes.

On July 6, 2023, the FDA granted lecanemab a traditional, full approval (Jul 2023 news).

At the November 2023 CTAD conference, Eisai presented results on subcutaneous dosing of lecanemab in the open-label extension phase of Clarity (Nov 2023 conference news). Participants were administered 720 mg weekly, in two doses, using either an injector pen or syringe and needle. After six months, subcutaneous delivery resulted in 11 percent higher blood exposure and more stable blood levels, compared to IV administration. Amyloid removal increased by 14 percent, and ARIA was slightly higher, both attributed to higher drug exposure.

At the same conference, post hoc analyses from Clarity's tau-PET substudy indicated that, among participants who began the study with low tau tangle load, more participants improved on the CDR-SB who were on lecanemab than were on placebo (Nov 2023 conference news). Lecanemab treatment stopped tangle accumulation over the course of the study, according to data presented at the 2024 AD/PD conference (Mar 2024 conference news). This occurred regardless of baseline tau load.

In February 2024, Eisai began post-marketing tracking of lecanemab safety in Japan, where it was approved in late 2023. This study will investigate ARIA and how it affects treatment continuation in 5,000 patients receiving lecanemab as part of routine clinical care. It will follow patients for three years. Completion is set for the end of 2027.

In March 2024, Eisai and Biogen applied for FDA approval of monthly maintenance infusions of lecanemab for patients previously treated on the biweekly regimen. The company also began to send data to the FDA on subcutaneous maintenance dosing. If approved, this would allow patients to dose themselves at home (May 2024 news).

In June 2024, DIAN-TU began an open-label study of lecanemab in people with early onset, familial AD who had completed a study with the discontinued amyloid antibody gantenerumab. The Amyloid Reduction Trial (ART) expects to enroll 65 people to receive intravenous lecanemab biweekly for a minimum of five years, against a primary outcome of time to progression on the CDR-SB. ART will also examine long-term safety and rates of ARIA, plaque removal, and downstream biomarkers. Completion is planned for November 2029.

On July 26, 2024, the European Medicines Agency recommended against approving Leqembi for use in Europe. Eisai has requested re-examination of the opinion (press release). In August 2024, Leqembi was approved in the United Arab Emirates. That month it was also approved in the United Kingdom, though the national health service will not cover its cost. China approved lecanemab in January 2024, South Korea in May, Israel in July.

At the August 2024 AAIC, Eisai presented data to support monthly maintenance dosing in trial participants who had cleared amyloid plaque (Aug 2024 conference news). When these patients stopped treatment, biomarkers of Aβ, tau, inflammation, and cognition worsened at the same rate as in placebo-treated patients, but in the open-label extension, treatment still slowed disease progression after three years. People treated at the earliest stages of AD had the biggest benefit. Disease modeling suggested 10 mg/kg monthly would be sufficient to sustain lecanemab’s effects on biomarkers and cognition.

Also according to reports at AAIC, two people died while receiving Leqembi in clinical care (Aug 2024 conference news). Both developed severe ARIA-E, possibly resembling cerebral amyloid angiopathy-related inflammation. In a published case, ischemic stroke and seizures were reported in a 71-year-old man who developed ARIA after lecanemab treatment (Gibson et al., 2024).

For all clinical trials of Leqembi/lecanemab, see clinicaltrials.gov.

Clinical Trial Timeline

Phase 1
Phase 2
Phase 3
Study completed / Planned end date
Planned end date unavailable
Study aborted

Sponsor	Clinical Trial	2008
Eisai Co., Ltd.	NCT01230853	N=80
Eisai Co., Ltd.	NCT01767311	N=856
Eisai Co., Ltd.	NCT03887455	N=1566

Last Updated: 10 Sep 2024

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Overview

Name: Verubecestat
Synonyms: MK-8931, MK-8931-009 , BACE inhibitor
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)
Company: Merck

Background

MK-8931 is a small-molecule inhibitor of BACE1 and BACE2. BACE1 is the β-secretase enzyme that cleaves the APP protein to release the C99 fragment of APP, which gives rise to various species of Aβ peptide during its subsequent cleavage by γ-secretase. The rationale of BACE inhibition is that it represents an upstream interference with the amyloid cascade, regardless of which species or aggregation states of Aβ then exert toxicity in the brain. BACE inhibition is sometimes envisioned as long-term maintenance therapy to limit Aβ production after an initial round of immunotherapy to remove existing amyloid deposits.

MK-8931 was developed preclinically with extensive use of a translational rhesus monkey model, in which a catheter implanted into the cisterna magna at the base of the neck enabled repeated CSF sampling for long-term monitoring studies without ill effects on the animal (see Dec 2007 conference news; Aug 2006 conference news).

To support the clinical development of MK-8931, Merck was using the FDA-approved amyloid PET tracer flutemetamol and, in 2013, forged an agreement with Luminex Corporation to develop a companion diagnostic device to measure Aβ and tau concentration in the CSF.

Findings

Phase 1 included four public studies of a total of 68 healthy controls, patients with mild to moderate Alzheimer's disease, and people with renal insufficiency, held in Japan and the United States, to gather initial data on safety, tolerability, and pharmacology (e.g. Min et al., 2019). One trial studied how renal insufficiency—a common condition in the aged—would alter clearance of the drug and inform dosing in future trials. Phase 1 trials tested single doses up to 450 mg and multiple doses from 12 to 150 mg/day. At the 2012 AAIC conference in Vancouver, Canada, MK-8931 was reported to have been generally safe, without discontinuations due to side effects, and to have reduced CSF Aβ concentration in AD patients.

Two Phase 1/2 dose-ranging trials further evaluated the tolerability and pharmacology of single and multiple doses, respectively, in 88 healthy adults. These results, too, were presented at the same conference to show good tolerability without withdrawals due to side effects, with dose-proportional increases in plasma and CSF exposure of the drug, and dose-dependent reduction in Aβ40 across the 2.5 to 550 mg/day administered to study volunteers. These studies used repeated CSF sampling, which found that CSF Aβ was reduced by up to 90 percent (see Jul 2012 conference news). An additional study confirmed similar PK and tolerability in healthy elderly volunteers (Forman et al., 2019).

In November 2012, Merck started EPOCH, an 18-month Phase 2/3 trial comparing 12, 40, or 60 mg/day of MK-8931 given as once-daily tablets to placebo in people with mild to moderate AD. EPOCH started out treating 200 people in Phase 2 and, after an interim safety analysis, expanded to Phase 3 with a total of 2,221 participants. This trial included conventional cognitive and functional primary outcomes, as well as substudies for biomarker outcomes indicating changes in brain amyloid, CSF tau levels, and brain volume. In response to questions about why this drug was being tested in mild to moderate AD rather than earlier-stage disease, Merck’s Johan Luthman said that the overall Phase 3 program included plans to test the drug across all disease stages, starting with mild to moderate, and that a trial in prodromal AD was planned (see Dec 2012 news). In December 2013, Merck announced that EPOCH had passed an interim safety evaluation and was proceeding to full enrollment and Phase 3. By October 2016 the trial was fully enrolled; data collection for the primary outcome was expected to wrap up in summer 2017. However, on 14 February 2017, Merck announced a premature end to this trial following an interim analysis (see Feb 2017 news). Results were presented at CTAD later that year (see Dec 2017 conference news), and formally published (Egan et al., 2018). A subsequent paper further detailed the safety data, noting particularly that while psychiatric side effects did not get worse over time, falls and injuries did (Egan et al., 2019).

In November 2013, Merck began the APECS trial in 1,500 participants with prodromal AD, aka mild cognitive impairment due to AD (aMCI). These patients have measurable cognitive deficits and a positive PET scan with the newly FDA-approved amyloid tracer flutemetamol, but are not functionally impaired. APECS compared 12 and 40 mg once-daily doses to placebo; treatment was to last for two years. APECS used change from baseline on the Clinical Dementia Rating Sum of Boxes (CDR-SB), a continuous measure, as its primary outcome. Secondary outcomes evaluated a range of newer measures, including a cognitive composite, CSF tau, brain imaging of hippocampal volume and amyloid load, and others. This trial was being conducted in more than 90 locations worldwide; it completed enrollment in November 2016 and was expected to complete data collection for its primary outcome in 2019.

In October 2016, Merck started an additional Phase 1 study in the United States to compare the liver metabolism of verubecestat in 32 people with hepatic insufficiency to people with normal liver function. In November 2016, Merck published data on verubecestat's discovery, in vitro characteristics, activity, and safety profile in rats and monkeys, as well as on pharmacokinetic modeling used for dose finding, and initial Phase 1 data for exposure to drug of up to one week (see Nov 2016 news on Kennedy et al., 2016).

In February 2018, APECS was discontinued (see Feb 2018 news) and Merck no longer listed verubecestat in its research pipeline. At the CTAD conference later that year, Merck reported that APECS participants on 40 mg verubecestat scored worse than the placebo group on the CDR-SB and ADAS-Cog13 starting at 13 weeks. The effect was small, with a Cohen’s d of 0.2, and did not progress over time. The 12 mg treatment group also performed slightly worse than controls, with the difference reaching significance at scattered time points. Both treatment groups scored worse than the placebo group on a functional measure, the ADCS-ADL, and reported more anxiety, depression, and sleep problems than controls (Nov 2018 conference news). The data have been published (Egan et al., 2019).

Merck and other companies continue to publish further analyses from BACE inhibitor trials (Dec 2020 news). Among the findings: In APECS, worsening on many secondary and exploratory cognitive tests was accompanied by improvement in verbal fluency (Wessels et al., 2020). In both EPOCH and APECS, verubecestat treatment came with more hippocampal and whole brain atrophy than placebo (see Dec 2019 news and Sur et al., 2020). The volume loss appeared by 13 weeks but did not progress. It occurred predominantly in amyloid-rich regions, but did not correlate with changes in amyloid load, cognitive decline, or biomarkers of neurodegeneration.

In EPOCH, another study found that verubecestat did not affect biomarkers of retinal degeneration, which did not track with changes in brain volume (Sergott et al., 2021).

For all trials on this drug, see clinicaltrials.gov.

Clinical Trial Timeline

Phase 1
Phase 2/3
Phase 3
Study completed / Planned end date
Planned end date unavailable
Study aborted

Sponsor	Clinical Trial	2009
Merck	NCT01496170	N=32
Merck	NCT01537757	N=12
Merck	NCT01739348	N=2221
Merck	NCT01953601	N=1500

Last Updated: 21 Jan 2021

Overview

Name: Riluzole
Synonyms: Rilutek®, RP 54274
Chemical Name: 6-trifluoromethoxy-2-benzothiazolamine
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline), Other (timeline)
Condition(s): Alzheimer's Disease, Parkinson's Disease, Amyotrophic Lateral Sclerosis, Huntington's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2), Parkinson's Disease (Discontinued), Amyotrophic Lateral Sclerosis (Approved), Huntington's Disease (Discontinued)
Company: Sanofi
Approved for: Amyotrophic Lateral Sclerosis in many countries

Background

Riluzole is the first FDA-approved medication for amyotrophic lateral sclerosis. It has been marketed in dozens of countries around the world since the late 1990s, and generic versions became available in the U.S. in 2013. Adverse events include blurred vision, difficulty breathing, weakness, dizziness, gastrointestinal discomfort, and others (Mayo Clinic Drug Information).

Riluzole's mechanism of action is not fully understood, but it has been shown repeatedly to modulate glutamate neurotransmission by inhibiting both glutamate release and postsynatpic glutamate receptor signaling. It also has been reported to inhibit voltage-gated sodium channels and to be neuroprotective by suppressing astrocytosis (Martin et al., 1993; Hubert et al., 1994; Carbone et al., 2012).

Glutamate-mediated toxicity has been implicated in Alzheimer’s disease. In two AD mouse models, riluzole administration, either before or during amyloid accumulation, prevented memory decline (Okamoto et al., 2018; Hascup et al., 2021). Riluzole was reported to reduce tau pathology and improve memory performance in TauP301L-expressing mice (Hunsberger et al., 2015). In rats, riluzole appeared to prevent age-related changes in gene expression similar to those seen in AD (Pereira et al., 2016).

Findings

Riluzole was approved for ALS because in several clinical trials it modestly extended survival or time to insertion of a breathing tube. Initial clinical trial reports of a slowing of muscle deterioration or symptomatic benefits were not corroborated in subsequent studies (Bensimon et al., 1994; Lacomblez et al., 1996). Pharmacoeconomics research has challenged the cost-effectiveness of riluzole treatment of ALS (Messori et al., 1999).

Riluzole completed Phase 3 clinical trials for the treatment of both Parkinson's and Huntington's diseases. Both programs had negative results and were discontinued (Bensimon et al., 2009; Landwehrmeyer et al., 2007).

Starting in April 2013, a Phase 2, six-month, investigator-initiated trial at Rockefeller University started testing riluzole in 50 patients with mild Alzheimer's who were already taking the cholinesterase inhibitor donepezil. It assessed changes in cognitive function, changes in brain concentration of the neuronal viability marker N-acetylaspartate (NAA) as measured by magnetic resonance spectroscopy (MRS), and changes in brain glucose metabolism as measured by FDG-PET. According to published results, 26 patients received riluzole 50 mg twice daily, and 24 received placebo tablets made at the Rockefeller University pharmacy; 22 and 20 completed the study. In riluzole-treated patients, glucose metabolism declined significantly less in the posterior cingulate compared to those on placebo. Trends toward less decline were seen in other prespecified brain regions, as well. FDG-PET positively correlated with cognitive performance. No differences were found in NAA levels, but glutamate was increased at three and six months of treatment (Matthews et al., 2021).

In addition, riluzole has been, or is being, investigated for a variety of neurologic and neuropsychiatric conditions in various investigator-initiated academic trials. These include autism, ataxia, Fragile X, multiple sclerosis, spinal cord injury, depression and bipolar disease, obsessive-compulsive disorder, spinal muscular atrophy, and others. Riluzole is also being tested against melanoma and other forms of cancer.

For details on clinical trials, see clinicaltrials.gov.

Clinical Trial Timeline

Phase 2
Study completed / Planned end date
Planned end date unavailable
Study aborted

Sponsor	Clinical Trial	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020	2021	2022	2023	2024	2025	2026	2027	2028	2029	2030	2031	2032	2033	2034
Rockefeller University	NCT01703117	N=48

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Clinical Trial Timeline

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